The invention relates to a process for the separation of a mixture of enantiomers.
Mixtures of enantiomers are obtained, for instance, in reactions that do not, or only to a small extent, proceed stereoselectively and in reactions in which there is no complete inversion or retention. The physical properties of enantiomers, such as boiling point, melting point and the like, are the same, so that a mixture of enantiomers cannot be separated using the customary separation techniques. In one of the methods for the separation of mixtures of enantiomers, for instance racemic mixtures, an optically active resolving agent is used to convert both enantiomers into the corresponding diastereomers. As the physical properties of these diastereomers do differ, the diastereomers can, at any rate in principle, subsequently be separated by, for instance, crystallization or chromatography, both diastereomers being obtained in substantially chemically pure and optically enriched form. The diastereomer can in a third step again be separated into the corresponding, optically enriched enantiomer and the optically active resolving agent. Several processes and optically active resolving agents for the separation of enantiomers are, for instance, extensively described in xe2x80x9cStereochemistry of Organic Compoundsxe2x80x9d by E. L. Eliel and S. H. Wilen (Wiley Interscience, 1994).
However, it is common knowledge that finding the right resolving agent for the separation of mixtures of enantiomers by crystallization of a mixture of diastereomers is in practice a laborious and highly time-consuming process, for a correct choice of the resolving agent cannot in advance be made, not even when applying advanced techniques such as, for instance, computer simulations or X-ray diffraction, and thus has to be found by trial and error for each mixture of enantiomers anew. This implies that for the separation of enantiomers via diastereomers often many experiments have to be conducted, while the individual experiments may take a long time on account of tedious crystallization. Moreover, in not nearly all the cases is a suitable resolving agent found. It will therefore be clear that the search for a good resolving agent for the separation of mixtures of enantiomers of a compound and the conditions under which good results are obtained is a time-consuming matter and the chance of success is unpredictable.
The subject invention therefore aims to provide a process by which a separation of enantiomers can be effected rapidly and with a high chance of success and by which the desired enantiomer is obtained with a high e.e.
According to the invention this is among other things achieved by means of a process for the separation of mixtures of enantiomers in which more than one resolving agent is used, of which at least one resolving agent is optically active, and which yields a diastereomer complex that contains at least two resolving agents in optically active form. It has been found that with the process according to the invention more often than in resolutions with a single resolving agent, directly a crystalline product is obtained instead of an oil, so that immediately the result of the experiment is known. Subsequent experiments can consequently be done in a shorter period of time. Moreover, the process according to the invention allows testing of several resolving agents and/or mixtures of enantiomers in one single experiment, so that the process according to the invention also allows rapid selection of suitable resolving agents. In addition, it has been found that in many cases the enantiomeric excess (e.e.) of the desired resolved enantiomer is higher when more than one resolving agent is used than when use is made of a single resolving agent. Furthermore it has been found that mixtures of enantiomers, which themselves cannot be resolved using a certain resolving agent, could be resolved when they were applied in combination with mixtures of enantiomers of similar structure.
According to the invention it is also possible to separate a mixture of enantiomer mixtures, that is, a mixture of two or more different chemical compounds in which both enantiomers of each compound occur, into substantially optically active enantiomers using one or more resolving agents,-of which at least one resolving agent is optically active. This is elucidated with reference to the following example, in which only one resolving agent is used: A mixture of the enantiomers of, for instance, compounds A, B and C (the mixture therefore contains 3 mixtures of enantiomers: 3 pairs of two enantiomers each) is separated into a mixture containing optically enriched enantiomers of compounds A, B and C, use being made of only a single optically active resolving agent. Of this second mixture subsequently the components A, B and C are separated from the resolving agent. After this, the components A, B and C are separated by means of the customary separation techniques. Of course, it is also possible to use a combination of different resolving agents. This way, in a single experiment many combinations can be rapidly tested.
The invention relates among other things to a diastereomer complex, for instance a salt, comprising at least three compounds of which at least one compound is a resolving agent in optically active form and at least one compound is an enantiomer in optically active form.
A diastereomer complex of one or more optically active resolving agents and one or more enantiomers is understood to mean complexes in which the resolving agent(s) and the enantiomer(s) are bonded via one or more non-covalent bonds, for instance van der Waals interactions, xcfx80xe2x80x94xcfx80-interactions, inclusion, ionogenic bonds, coordination bonds, hydrogen bonds and/or a combination of such bonds.
As resolving agent use can be made of any compound that is suitable for converting a mixture of enantiomers via precipitation into a diastereomeric salt containing a mixture of enantiomers with a higher enantiomeric excess. The resolving agent may contain a metal, optionally with the associated ligands. Preferably, as optically active resolving agent use is made of a resolving agent with the highest possible e.e., for instance an e.e.  greater than 95%, in particular  greater than 98%, more in particular  greater than 99%.
The term enantiomer in this context refers to the mixture of enantiomers to be enriched. As mixture of enantiomers in principle all chiral compounds, in practice usually compounds containing at least one asymmetrical carbon atom, can be used. The enantiomers can for instance be compounds that contain at least an acid group, an amino group, a hydroxy group and/or a thiol group.
In principle a chemical compound that can be appropriately used as a mixture of enantiomers to be separated with an appropriate resolving agent, also represents an appropriate resolvent agent to be used in the separation of a mixture of enantiomers.
In the framework of this invention the term mixture of enantiomers means a mixture of the enantiomers of an optically active compound in any ratio.
Naturally, in the framework of this invention the same holds with respect to the separation of a mixture of enantiomers which already has a certain enantiomeric excess as for racemic mixtures.
In a particularly suitable embodiment the mixtures of enantiomers are separated via salt formation. Examples of mixtures of enantiomers that can suitably be separated via salt formation are acids, and bases in particular carboxylic acids, phosphoric acids, sulphonic acids, phosphinic acids, sulphinic acids, amines, acidic alcohols, amino acids, amino alcohols and acidic thiols.
Other examples of ways in which mixtures of enantiomers can suitably be separated according to the invention are separations via inclusion compounds, for which in principle any chiral compound forming an inclusion compound can be used, or separation via metal complexes, for instance as described in J. A. Gladysz and B. J. Boone, Angew. Chem. Int. Ed. Engl. 36, p. 576-577, 1997.
As an example of a possible use of the process according to the invention, the invention will now be elucidated with reference to the separation of a racemic mixture of an amine using at least two optically active acids or using at least one optically active acid and a non-optically active acid. A first commercially interesting use of the process according to the invention is the screening of resolving agents. In practice this is usually done at lab scale, with various acids, for instance 2-20, in particular 2-12, more in particular 2-6, simultaneously being used as resolving agents. The combination of acids found in the complex precipitated usually offers the best prospects of a good result, it probably being possible in a number of cases to leave out acids that are found in the complex in small amounts. Of course it is also possible that only one resolving agent, in this specific case one acid, is found in the complex. In that case the resolving agent preferably used will contain only one component.
The acids that upon screening at lab scale are selected may subsequently be used as agent in the form of a mixture of at least two, for instance 2-6, in particular 2-3 acids in the separation of a racemic mixture of the amine on an industrial scale. An optically active amine and a mixture of at least 2 acids are obtained from the resulting diastereomer mixture of salts.
Preferably, the resolving agents are of the same type, for instance resolving agents within a certain group. Examples of groups of resolving agents that can suitably be used in the process according to the invention are:
Substituted phosphoric acids, for example phosphoric acids of formula S1: 
where R1 and R2 each independently represent H, an alkyl group or an aryl group;
Optically active substituted tartaric acids, for instance tartaric acids of formula S2: 
where R1 and R2 are as defined above;
Substituted xcex1-hydroxycarboxylic acids, for instance mandelic acids of formula S3; 
where R1 and R2 are as defined above;
N-acylamino acids, substituted or not, for instance N-acylamino acids of formula S4: 
where R3 has a fixed meaning within a group, chosen from an alkyl group or an aryl group, and R4 represents an aryl group, for instance an R1 and R2 substituted phenyl group with R1 and R2 as defined above, or an alkyl group, for instance an amino acid radical as occurring in natural amino acids, or where R4 has a fixed meaning within a group, chosen from an aryl group, for instance an R1 and R2 substituted phenyl group with R1 and R2 as defined above, or an alkyl group, for instance an amino acid radical of natural amino acids, and R3 represents an alkyl group or an aryl group.
A special example is acylated protein hydrolysate. or of formula S5 (N-benzyloxycarbonyl amino acids): 
where R4 is as defined above;
N-carbamoyl amino acids, substituted or not, for instance N-carbamoyl amino acids of formula S6: 
where R4 is as defined above. A special example is carbamoylated protein hydrolysate;
Substituted phenalkylamines, for instance phenalkylamines of formula S7: 
where R1 and R2 may vary within a group as defined above and R5 has a fixed meaning, chosen from alkyl, or R1 and R2 are fixed choices from the groups as defined above and R5 varies within the alkyl group;
Amino acid amides, substituted or not, for instance amino acid amides of formula S8: 
where R4 is as defined above, and R6 and R7 are chosen independently of each other from H and alkyl;
Substituted N-glucosamines, for instance N-glucosamines of formula S9: 
where R5 is as defined above;
Aryloxypropionic acids, for instance aryloxypropionic acids of formula S10: 
where R1 and R2 are as defined above;
Optically active ethers of tartaric acids, for instance ethers of formula S11: 
where R8 is preferably methyl or benzyl;
optically active acetals of tartaric acids, for instance acetals of formula S12: 
where R3 is as defined above and R3xe2x80x2 independently represents the same groups and is not equal to R3;
optically active alkanoylesters of tartaric acids, for instance of formula S13: 
where R5 is as defined above;
phenylaminopropane diols, for instance of formula S14: 
where R1 and R2 are as defined above.
The substituents Ri with i=1-8 preferably contain 1-30, particularly 1-20 C-atoms and may optionally be substituted with an alkyl group, alkoxy group, carboxyl group, alkoxycarbonyl group, amino group, nitro group, thio group, thioalkyl group, nitrile group, hydroxy group, acyl group or halogen.
Examples of suitable mixtures of enantiomers are:
xcex1-amino acids and their derivatives with as formula (E1): 
where:
R4 is as defined above
R6 and R7 are as defined above
R9 stands for OH, alkoxy, NH2 
R10 stands for H, alkyl and aryl
and R4 is not the same as R10 
xcex1-aminonitriles, for instance of formula (E2): 
where R4, R6, R7 and R10 are as defined above;
xcex2-amino acids (and derivatives) for instance of formula (E3) 
where R4, R6, R7 and R8 are as defined above. phenalkylamines, for instance of formula E4: 
where R1, R2, R5, R6 and R7 are as defined above; piperazines, for instance piperazines of formula E5: 
where R10 is as defined above and R11 and R12 independently represent an alkyl group, aryl group or COR9 group;
piperidines, for instance piperidines of formula E6: 
where R10 is as defined above and R13 and R14 each independently represent R11, OH or an alkoxy group; pyrrolidines, for instance pyrrolidines of formula E7: 
where R10, R13 and R14 are as defined above;
morpholines, for instance morpholines of formula E8: 
where R10, R11, and R12 are as defined above;
diamines, for instance diamines of formula E9: 
where m and n each independently is 0-5 and where R11 is as defined above and R6xe2x80x2 and R7xe2x80x2 independently thereof represent the same groups as R6 and R7;
ephedrines, for instance ephedrines of formula E10: 
where R1, R2, R6 and R7 are as defined above.
amino alcohols or amino ethers, for instance of formula E11a, E11b or E11c: 
where n is 0-10, R15=H or alkyl and where R10xe2x80x2 independently thereof represents the same groups as R10 and R6, R7, R10, R3 and R3xe2x80x2 are as defined above;
1-(2-naphthyl)alkylamines, for instance 1-(2-naphthyl)alkylamines of formula E12: 
where R1, R2, R5, R6 en R7 are as defined above;
aliphatic amines, for instance aliphatic amines of formula E13: 
where R6, R7, and R10 are as defined above, and R10xe2x80x2 and R10xe2x80x3 are chosen from the same group as R10 and are not the same as each other and as R10;
phosphoric acids, for instance phosphoric acids of formula (E14): 
where R1 are R2 as defined above;
carboxylic acids, for instance carboxylic acids of formula E15: 
where R3 en R3xe2x80x2 are as defined above;
substituted butane dicarboxylic acids for instance of formula (E16): 
where R3 en R4 are as defined above;
aromatic or aliphatic hydroxycarboxylic acids or derivatives thereof, in particular substituted mandelic acids, for instance xcex1-hydroxycarboxylic acids of formula E17: 
where R10, R10xe2x80x2 and R15 are as defined above and R10 and R10xe2x80x2 are different;
sulphonic acids, in particular (substituted) camphor-sulphonic acids or (substituted) 1-phenylalkane-sulphonic acids of formula E18: 
where R1, R2 and R3 are as defined above; 2-aryloxyalkanoic acids, in particular 2-aryloxypropionic acids of formula E19: 
where R1 and R2 are as defined above; biaryl biacids, in particular biaryl bicarboxylic acids of formula E20: 
where R1 and R2 are as defined above and R1xe2x80x2 and R2xe2x80x2 are independently thereof chosen from the same groups as R1 and R2;
substituted bi(hetero)aryldifosfinic oxides,
particularly binaphthalene difosfinic oxides of formula E21: 
wherein R1 and R2 are as defined above and are situated arbitrarily on the naphthalene skeleton, and Ar represents a (hetero)aryl group.
The substituents Ri with i=1-15 and Ar preferably contain 1-30, in particular 1-20 C-atoms and may or may not be substituted with an alkyl group, alkoxy group, carboxyl group, alkoxycarbonyl group, amino group, nitro group, thio group, thioalkyl group, nitrile group, hydroxy group, acyl group or halogen.
As is known to one skilled in the art, during crystallization inclusion of one or more solvent molecules may also take place. The diastereomer complex according to the invention may therefore also contain one or more molecules of a solvent. The ratio of the resolving agents to each other may vary within a wide range, with, in the case of salt formation, the sum of the acid groups and the sum of the basic groups in the complex having to be equal. It has, surprisingly, been found that after one or two recrystallizations the diastereomers according to the invention remain constant as regards the ratio of the resolving agents in the diastereomer upon further recrystallizations. This proves that the widespread ratio of resolving agents that is found is not the result of simple inclusion, for instance due to too rapid crystallization.
The invention also relates to an agent for separating a mixture of enantiomers, the agent comprising at least two resolving agents of which at least one is optically active. Preferably, the agent contains at least two resolving agents of the same type.
The invention also relates to a process for separating a mixture of enantiomers. This process is characterized in that the mixture of enantiomers is contacted in a suitable solvent with at least two resolving agents, at least one of which is optically active, yielding the diastereomer complex as described above. The sequence in which this takes place is not critical. In the process use is made of standard procedures and conditions that are generally known for separation of enantiomers via the formation of diastereomers. One skilled in the-art can simply find out which principles and methods used for optimization of classical resolution processes can also be applied to the process according to the subject invention. One option is, for instance, to replace a portion of the resolution acids or bases with mineral acids or bases in order to optimize the use of the expensive resolving agents. Also, the result of the resolution may be strongly dependent on the molar ratio of resolving agent to the racemate. Such ratio may for instance be varied between 0,5 and 2.
Although this is not preferred, it is also possible to resolve a mixture of enantiomers by first adding one or more resolving agent(s) and, when no crystallization of a diastereomer takes place, add one or more further resolving agent(s), etc. This can be done by, for instance, adding 2-21, preferably 2-13 and in particular 2-7 resolving agents. It will be clear to one skilled in the art that this process is more time-consuming, for which reason the resolving agents are preferably added simultaneously, certainly at lab scale.
On an industrial scale the addition of the resolving agents will be chosen so that the crystallization is controllable and, for instance, no crystallization takes place at undesirable places in the installation and also the heat development per unit of time remains controllable. To achieve this, dosing in time of the combination of resolving agents can be adapted. Optionally, the resolving agents are added one after the other. The optimum way of adding the resolving agents can simply be determined by one skilled in the art.
The optically active resolving agents according to the invention preferably have an e.e. larger than 95%, in particularly larger than 98%, more in particular larger than 99%.
It has, surprisingly, also been found that when several optically active resolving agents are applied, these need not necessarily have the same absolute configuration. It has, for instance, been found that when use is made of three resolving agents A, B and C, a separation was possible both when A and B had, for instance, the S-configuration and C the R-configuration, and when A, B and C all had the S-configuration. The complex formed in both cases contained A and B as well as C, C in both cases having a different configuration. This may be useful in the cases where only one enantiomer of the relevant resolving agent is well obtainable.
Preferably, substantially only the diastereomer complex according to the invention crystallizes out with the highest possible e.e. of the separate compounds, following which it can be isolated using customary techniques. This may also involve chemical purification of the diastereomer complex. The process according to the invention can therefore also be applied to effect chemical purification of the mixture of enantiomers.
The conversion of the above-mentioned diastereomer complex to the enantiomers present in it is carried out in ways that are generally known to one skilled in the art, for instance by acid or base treatment followed by extraction, distillation or chromatography.
From practice it is known that the use of a mixture of two or more different solvents in crystallizations may sometimes give better results. If a mixture of solvents is used, this mixture for instance consists of 2-5 different solvents, and in particular of 2-3. The process according to the subject invention can therefore also be carried out using a mixture of two or more different solvents.
The invention will be elucidated on the basis of examples.
Definitions and Syntheses
P-mix
were prepared and resolved according to Ten Hoeve and Wijnberg, U.S. Pat. No. 4,814,477.
W-mix
W1, Dibenzoyltartaric acid,
W2, Di-p-toluoyltartaric acid were obtained from Aldrich.
W3, Di-p-anisoyltartaric acid was prepared and resolved following literature procedures.
A-mix
A1, Mandelic acid was obtained from Aldrich,
A2, p-methylmandelic acid
A3, p-fluoromandelic acid
were prepared and resolved following literature procedures.
Other mandelic acid analogs, p-methoxymandelic acid, p-bromomandelic acid and p-chloromandelic acid were prepared and resolved following literature procedures.
PEA I-mix
p-Br-PEA, p-Br-phenethylamine was prepared according to: J.A.C.S. 105, 1578-84 (1983) via Leuckhart synthesis from commercially available p-Br-acetophenone (Aldrich). Resolution see Example I.3; Table 1.
p-Cl-PEA, p-Cl-phenethylamine was prepared as above from p-Cl-acetophenone (Aldrich). Resolution see Example I.6 and I.7; Table 1.
p-CH3-PEA, p-CH3-phenethylamine was prepared as above from p-CH3-acetophenone (Aldrich). Resolution see Example I.4 and I.5; Table 1.
Resolution of rac. PEA I-mix see E; Examples IX-XI.
PEA II-mix
PEA, phenethylamine (Aldrich),
p-NO2-PEA, p-NO2-phenethylamine and
o-NO2-PEA, o-NO2-phenethylamine
p-NO2-PEA and o-NO2-PEA were prepared as a 1:1 mixture as described in the literature from optically pure PEA (Aldrich).
The mixture is applied with a ratio
PEA: p-NO2-PEA: o-NO2-PEA=1:1:1
PEA IIA-mix,
p-NO2-PEA and o-NO2-PEA as 1:1 mixture.
PEA IIB-mix
PEA and p-NO2-PEA as 1:1 mixture
Pure p-NO2-PEA was obtained via crystallization of the
HCl salt.
PEA III-mix
m-MeO-PEA, m-CH3O-phenethylamine
m-Cl-PEA, m-Cl-phenethylamine
m-Br-PEA, m-Br-phenethylamine
were synthesized following the same procedure used for the synthesis of the para analogues.
Resolution or rac. PEA III-mix see E; Example XII
Other PEA analogs (from the o-, m-, and p-series) were synthesized following the known procedure.
BA I-mix
xcex1-Me-BA, xcex1-methylbenzylamine (Aldrich);
xcex1-Et-BA, xcex1-ethylbenzylamine and
xcex1-iP-BA, xcex1-isopropylbenzylamine
were synthesized following literature procedures.
Resolution of BA I-mix see E; Example XIII
A. Small Scale Resolution of Amines with the P-mix, W-mix and A-mix